Anti-Aging Effects of GDF11 on Skin.
Human skin is composed of three layers: the epidermis, the dermis, and the hypodermis. The epidermis has four major cell layers made up of keratinocytes in varying stages of progressive differentiation. Skin aging is a multi-factorial process that affects every phase of its biology and function. The expression profiles of inflammation-related genes analyzed in resident immune cells demonstrated that these cells have a strong ability to regenerate adult skin stem cells and to produce endogenous substances such as growth differentiation factor 11 (GDF11). GDF11 appears to be the key to progenitor proliferation and/or differentiation. The preservation of youthful phenotypes has been tied to the presence of GDF11 in different human tissues, and, in the skin, this factor inhibits inflammatory responses. The protective role of GDF11 depends on a multi-factorial process implicating various types of skin cells such as keratinocytes, fibroblasts and inflammatory cells. GDF11 should be further studied for the purpose of developing novel therapies for the treatment of skin diseases.


US-guided botulinum toxin injection for excessive drooling in children.
We aimed to evaluate the safety and efficacy of botulinum toxin A (BTX-A) injections under ultrasonography (US) guidance for children with excessive drooling. Between January 2006 and January 2011, 44 BTX-A injections into bilateral submandibular glands were performed in 20 children (mean age, 9.1 years; range, 3-16 years; gender, 15 boys and 5 girls) under intravenous sedation. Efficacy of the injections was evaluated 4-12 weeks after the injection. Severity of drooling was assessed using the Teacher Drooling Scale (TDS). If the patient or the patient's caregiver reported a good initial response, injections were then repeated periodically when drooling reached the preinjection score. If there was no response or suboptimal response, a booster injection of BTX-A was given after one month. Technical success rate was 100%. No procedure-related major or minor complication was detected. One family (5%) reported intermittent problems with swallowing due to viscous saliva. A successful outcome was defined as a minimum two point reduction in TDS score. This outcome occurred for 8 of 20 patients four weeks after the first injection. After consecutive sessions, clinical success was achieved at the end of the 12 weeks for 16 patients (80%). The mean TDS score decreased from 4.75 to 2.1 at the end of the study for all patients (P < 0.05). Four patients did not respond to BTXA injection. Submandibular resection was applied to 3 of 4 unresponsive patients. Two patients had complete remission after surgery, but one patient showed excessive drooling that could not be controlled. US-guided submandibular BTX-A injection is a safe and effective procedure in treating drooling in children. It can be performed under intravenous sedation and does not require general anesthesia.


High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series.
The impact of treatment options on survival and late neurologic toxicity was investigated in a series of patients with primary cerebral lymphoma (PCL) and no known cause of immunosuppression. Prognostic factors for survival and treatment-induced late neurotoxicity were investigated in a retrospective series of 226 patients with PCL. With a median follow-up of 76 months, the median overall survival was 16 months and 5-year survival was 19%. In a univariate analysis, age greater than 60 years, performance status, CSF protein level greater than 0.6 g/L, involvement of corpus callosum or subcortical grey structures, detectable lymphoma cells in CSF, increased serum lactate dehydrogenase (LDH), but not histological subtype, were significantly correlated with a poor survival. Treatment with chemotherapy versus radiotherapy alone (P = .05), high-dose methotrexate (HDMTX; P = .0007), and cytarabine (P = .04) correlated with a better survival in univariate analysis. Using the Cox model, age, performance status, and CSF protein were independently correlated with survival. After adjustment of these factors, treatment with an HDMTX-containing regimen remained the only treatment-related factor independently correlated with survival (P = .01). The projected incidence of treatment-induced late neurotoxicity was 26% at 6 years in this series, with a median survival from the diagnosis of late neurotoxicity of 12 months. Treatment with radiotherapy followed by chemotherapy was the only parameter correlated with late neurotoxicity in multivariate analysis (relative risk, 11.5; P = .0007). Patients with PCL treated with regimens that included HDMTX followed by radiotherapy have an improved survival, but not a higher risk of late neurotoxicity as compared with other treatment modalities in this series.


Influence of poly(ADP-ribose) polymerase on the enzymatic synthesis of SV40 DNA.
The influence of poly(ADP-ribose) polymerase (PARP) on the replication of DNA containing the SV40 origin of replication has been examined. Extensive replication of SV40 DNA can be carried out in the presence of T antigen, topoisomerase I, the multimeric human single strand DNA-binding protein (HSSB), and DNA polymerase alpha-DNA primase (pol alpha-primase) complex (the monopolymerase system). In the monopolymerase system, both small products (Okazaki fragments), arising from lagging strand synthesis, and long products, arising from leading strand synthesis, are formed. The synthesis of long products requires the presence of relatively high levels of pol alpha-primase complex. In the presence of PARP, the synthesis of long products was blocked and only small Okazaki fragments accumulated, arising from the replication of the lagging strand template. The inhibition of leading strand synthesis by PARP can be effectively reversed by supplementing the monopolymerase system with the multimeric activator 1 protein (A1), the proliferating cell nuclear antigen (PCNA) and PCNA-dependent DNA polymerase delta (the dipolymerase system). The inhibition of leading strand synthesis in the monopolymerase system was caused by the binding of PARP to the ends of DNA chains, which blocked their further extension by pol alpha. The selective accumulation of Okazaki fragments was shown to be due to the coupled synthesis of primers by DNA primase and their immediate extension by pol alpha complexed to primase. PARP had little effect on this coupled reaction, but did inhibit the subsequent elongation of products, presumably after pol alpha dissociated from the 3'-end of the DNA fragments. PARP inhibited several other enzymatic reactions which required free ends of DNA chains. PARP inhibited exonuclease III, DNA ligase, the 5' to 3' exonuclease, and the elongation of primed DNA templates by pol alpha. In contrast, PARP only partly competed with the elongation of primed DNA templates by the pol delta elongation system which required SSB, A1, and PCNA. These results suggest that the binding of PARP at the ends of nascent DNA chains can be displaced by the binding of A1 and PCNA to primer ends. HSSB can be poly(ADP-ribosylated) in vivo as well as in vitro. However, the selective effect of PARP in blocking leading strand synthesis in the monopolymerase system was shown to depend primarily on its DNA binding property rather than on its ability to synthesize poly(ADP-ribose).


Nationwide distribution of cardiovascular practice in Japan - results of Japanese circulation society 2010 annual survey.
The geographic distribution of cardiovascular (CV) health-care services has not been assessed systematically. Data of the Japanese Circulation Society (JCS) annual survey were provided to the JCS working group with the permission of the JCS Scientific Committee. The status of CV practice in 2010 was then assessed in 47 prefectures retrospectively, along with national census and gross domestic product (GDP) data. The surveyed indices included resources (hospitals, beds and cardiologists), burden (number of inpatients), and outcome (CV mortality and autopsy) in each prefecture, which correlated well with respective populations or GDP. Inequality of geographic distribution was evident for pediatrics among the 47 prefectures, according to Lorenz curve, Gini coefficient or the maximum/minimum ratio for each index. According to the Gini coefficients, only the number of inpatients (medical or acute myocardial infarction) and beds for the total number of general hospitals or the hospitals surveyed in the present JCS study were lower than expected with regard to GDP. Geographic disparity of CV resources or burden was larger in pediatrics than in CV medicine or surgery. Improvement of equality in CV practice with regard to appropriateness and quality are the coming challenges for the JCS.


Anxiety and Sleep Disturbances Among Health Care Workers During the COVID-19 Pandemic in India: Cross-Sectional Online Survey.
The COVID-19 pandemic caused by SARS-CoV-2 has become a serious concern among the global medical community and has resulted in an unprecedented psychological impact on health care workers, who were already working under stressful conditions. In this study, we aimed to evaluate and measure the effects of the COVID-19 pandemic on the anxiety levels and sleep quality among health care workers in India, as well as to determine how the unavailability of personal protective equipment affects their willingness to provide patient-related care. We conducted an online cross-sectional study using piloted, structured questionnaires with self-reported responses from 368 volunteer male and female health care workers in India. Study participants were identified through social networking platforms such as Facebook and WhatsApp. The survey evaluated the participants' degree of signs and symptoms of anxiety and sleep quality based on the 7-item Generalized Anxiety Disorder (GAD-7) scale and single-item Sleep Quality Scale, respectively. Information on the availability of personal protective equipment was collected based on responses to relevant survey questions. The majority of health care workers (126/368, 34.2%) were in the age group 45-60 years, and 52.2% (192/368) were doctors. Severe anxiety (ie, GAD-7 score >10) was observed among 7.3% (27/368) health care workers, whereas moderate, mild, and minimal anxiety was observed among 12.5% (46/368), 29.3% (108/368), and 50.8% (187/368) health care workers, respectively. Moreover, 31.5% (116/368) of the health care workers had poor-to-fair sleep quality (ie, scores <6). Univariate analysis showed female gender and inadequate availability of personal protective equipment was significantly associated with higher anxiety levels (P=.01 for both). Sleep disturbance was significantly associated with age <30 years (P=.04) and inadequate personal protective equipment (P<.001). Multivariable analysis showed that poorer quality of sleep was associated with higher anxiety levels (P<.001). The COVID-19 pandemic has potentially caused significant levels of anxiety and sleep disturbances among health care workers, particularly associated with the female gender, younger age group, and inadequate availability of personal protective equipment. These factors put health care workers at constant risk of contracting the infection themselves or transmitting it to their families. Early identification of at-risk health care workers and implementation of situation-tailored mitigation measures could help alleviate the risk of long-term, serious psychological sequelae as well as reduce current anxiety levels among health care workers.


Prevalence of biofilm-forming bacteria in chronic rhinosinusitis.
Recently, biofilms have been implicated in the pathogenesis of recalcitrant chronic rhinosinusitis (CRS). We sought to determine the prevalence of biofilm-forming cultures obtained from patients with CRS and clinical factors that may contribute to biofilm formation. Endoscopically guided sinonasal cultures were obtained in duplicate from CRS patients with evidence of mucopurulence. Bacterial swabs were sent for microbiological characterization and were simultaneously evaluated for biofilm-forming capacity by a modified Calgary Biofilm Detection Assay. Biofilm formation was based on concomitant values of biofilm-forming Pseudomonas aeruginosa O1 (PAO1) (positive control) and non-biofilm-forming mutants sad-31 (type IV pili) and sad-36 (flagella K; negative control). Samples, with growth greater than the sad-31 mutant, were designated as biofilm formers. Sinonasal cultures were obtained from 157 consecutive patients (83 female patients) over a 4-month period. Forty-five samples (28.6%) showed biofilm formation. Among patients with a prior history of functional endoscopic sinus surgery (FESS), 30.7% (n = 42) showed biofilm growth. For patients naive to surgical intervention (n = 20), only 15% showed biofilm formation. A positive, statistically significant correlation existed between biofilm formation and number of prior FESS procedures. Polymicrobial cultures, Pseudomonas aeruginosa, and/or Staphylococcus aureus comprised 71% of samples. Chi-squared analysis showed an association with prior infections, but not with any pharmacologic therapy or comorbidies. We show a high percentage of CRS patients (28.6%) whose sinonasal mucopurulence has biofilm-forming capacity. Postsurgical patients had a high prevalence of biofilm-forming bacteria, a possible reflection of the severe nature of their disease. Additional studies are warranted.


Pitfalls in precision stereotactic surgery.
Precision is the ultimate aim of stereotactic technique. Demands on stereotactic precision reach a pinnacle in stereotactic functional neurosurgery. Pitfalls are best avoided by possessing in-depth knowledge of the techniques employed and the equipment used. The engineering principles of arc-centered stereotactic frames maximize surgical precision at the target, irrespective of the surgical trajectory, and provide the greatest degree of surgical precision in current clinical practice. Stereotactic magnetic resonance imaging (MRI) provides a method of visualizing intracranial structures and fiducial markers on the same image without introducing significant errors during an image fusion process. Although image distortion may potentially limit the utility of stereotactic MRI, near-complete distortion correction can be reliably achieved with modern machines. Precision is dependent on minimizing errors at every step of the stereotactic procedure. These steps are considered in turn and include frame application, image acquisition, image manipulation, surgical planning of target and trajectory, patient positioning and the surgical procedure itself. Audit is essential to monitor and improve performance in clinical practice. The level of stereotactic precision is best analyzed by routine postoperative stereotactic MRI. This allows the stereotactic and anatomical location of the intervention to be compared with the anatomy and coordinates of the intended target, avoiding significant image fusion errors.


EVALUATION OF A MODIFIED EPWORTH SLEEPINESS SCALE TO RELIABLY ASSESS EXCESSIVE DAYTIME SLEEPINESS IN LOW-INCOME COUNTRIES: RESULTS FROM THE BENIN SOCIETY AND SLEEP (BESAS) STUDY.
The Epworth Sleepiness Scale (ESS) is a tool widely used to assess excessive daytime sleepiness. Unfortunately, it is not reliable in low-income countries where situations such as reading a book, watching TV or driving a car are not common. The aim of this study was thus to assess the performance of a modified version of the Epworth scale in a low-income country. We used data from the Benin Society and Sleep (BeSAS) study where the ESS and a modified ESS (mESS) were administered to participants. In the mESS, questions four questions over eight were redesigned to reflect common living situations in Benin. The internal coherence of the mESS was assessed using the Cronbach alpha coefficient (CAC). The discriminatory ability of the scale was assessed by comparing the mean scores according to reported sleep quality, insomnia complaints and apnea-hypopnea index (AHI). A total of 2909 participants were recruited, 1129 were male (38.9%) with a mean age (SD) of 44.7 (14.5) y. Overall, 52.4% (1526) completed all the mESS questions while 453 (15.6%) completed the standard ESS. The CAC of the mES was 0.86 showing good internal coherence. Concerning the discriminatory ability, mean scores for mESS were 7.8 for participants with ISI < 8 vs 9.2 for participants with ISI≥8 (p<0.001), 7.8 for participants withPSQI<5 vs 8.3 for participants with PSQI≥5 (p=0.03). No difference was found when comparing the participants participants using different cut-offs of AHI (15 and 30). The mES is more reliable than ES in the Beninese population. mESS shows good internal coherence and differentiates between insomniacs vs non-insomniacs and between good and poor sleepers. Although the mES is not a perfect score, it appears more relevant in the Benin population than the original Epworth scale but needs further validation/improvement in other low-income countries.


Current perspectives on imaging cardiac stem cell therapy.
Molecular imaging is a new discipline that makes possible the noninvasive visualization of cellular and molecular processes in living subjects. In the field of cardiovascular regenerative therapy, imaging cell fate after transplantation is a high priority in both basic research and clinical translation. For cell-based therapy to truly succeed, we must be able to track the locations of delivered cells, the duration of cell survival, and any potential adverse effects. The insights gathered from basic research imaging studies will yield valuable insights into better designs for clinical trials. This review highlights the different types of stem cells used for cardiovascular repair, the development of various imaging modalities to track their fate in vivo, and the challenges of clinical translation of cardiac stem cell imaging in the future.


The Influence of Sitting, Standing, and Stepping Bouts on Cardiometabolic Health Markers in Older Adults.
Aside from total time spent in physical activity behaviors, how time is accumulated is important for health. This study examined associations between sitting, standing, and stepping bouts, with cardiometabolic health markers in older adults. Participants from the Mitchelstown Cohort Rescreen Study (N = 221) provided cross-sectional data on activity behaviors (assessed via an activPAL3 Micro) and cardiometabolic health. Bouts of ≥10-, ≥30-, and ≥60-min sitting, standing, and stepping were calculated. Linear regression models were fitted to examine the associations between bouts and cardiometabolic health markers. Sitting (≥10, ≥30, and ≥60 min) and standing (≥10 and ≥30 min) bouts were detrimentally associated with body composition measures, lipid markers, and fasting glucose. The effect for time spent in ≥60-min sitting and ≥30-min standing bouts was larger than shorter bouts. Fragmenting sitting with bouts of stepping may be targeted to benefit cardiometabolic health. Further insights for the role of standing need to be elicited.


A tissue-specific, injectable acellular gel for the treatment of chronic vocal fold scarring.
Gel-based injectable biomaterials have significant potential for treating vocal fold defects such as scarring. An ideal injectable for vocal fold lamina propria restoration should mimic the microenvironment of the lamina propria to induce scarless wound healing and functional tissue regeneration. Most current synthetic or natural injectable biomaterials do not possess the same level of complex, tissue-specific constituents as the natural vocal fold lamina propria. In this study we present a newly-developed injectable gel fabricated from decellularized bovine vocal fold lamina propria. Blyscan assay and mass spectrometry indicated that the vocal fold-specific gel contained a large amount of sulfated glycosaminoglycans and over 250 proteins. Gene Ontology overrepresentation analysis revealed that the proteins in the gel dominantly promote antifibrotic biological process. In vivo study using a rabbit vocal fold injury model showed that the injectable gel significantly reduced collagen density and decreased tissue contraction of the lamina propria in vocal folds with chronic scarring. Furthermore, this acellular gel only elicited minimal humoral immune response after injection. Our findings suggested that the tissue-specific, injectable extracellular matrix gel could be a promising biomaterial for treating vocal fold scarring, even after the formation of mature scar. STATEMENT OF SIGNIFICANCE: Vocal fold lamina propria scarring remains among the foremost therapeutic challenges in the management of patients with voice disorders. Surgical excision of scar may cause secondary scarring and yield inconsistent results. The present study reports an extracellular matrix-derived biomaterial that demonstrated antifibrotic effect on chronic scarring in vocal fold lamina propria. Its injectability minimizes the invasiveness of the delivery procedure and the degree of mucosal violation. In this work we also describe a new methodology which can more accurately identify proteins from the complex mixture of an acellular extracellular matrix gel by excluding interfering peptides produced during the enzymatic digestion in gel fabrication.


Personalizing protocol-driven care: the case of specialist heart failure nurses.
This paper is a report of a study conducted to explore how specialist heart failure nurses negotiate treatment advice with patients, in the context of an increasing expectation that clinical staff in the National Health Services will follow guidelines in their daily work. The development of specialist nurse roles has given rise to questions about their compatibility with patient-centred care. However, research has revealed little about how specialist nurses balance clinical guidelines with traditional caring tasks. Semi-structured interviews (n = 10) were conducted with specialist heart failure nurses in northern England recruited from a heart failure specialist nursing contact list. In addition, non-participant observations were carried out on nurse-patient consultations (n = 16) in one regional nurse-led heart failure clinic. Data were collected between 2003 and 2005, and analysed using a variation of grounded theory. Heart failure nurses sought to combine traditional caring work with the wider goal of improving patient outcomes by 'personalizing' their advice to patients and presenting their heart failure as 'typical'. They accommodated protocol-driven care into their daily routines, and perceived no disjuncture between evidence-based practice and patient-centredness. However, their approach allowed little space for the exploration of each patient's own priorities about their illness. There is a need both to re-examine the appropriateness of traditional caring concepts, and to reflect on the need to incorporate patients' own values into the consultation process.


Progress in the initial management of Hodgkin's Lymphoma.
Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy composed of two distinct disease entities; the more commonly diagnosed classical HL and the rare nodular lymphocyte predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich HL are subgroups under the designation of classical HL. An accurate assessment of the stage of disease in patients with HL is critical for the selection of appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence are used to optimize therapy for patients with limited or advanced stage disease and predict their outcomes while reducing the toxicities. Initial therapy for HL patients is based on the histology, anatomical stage and the presence of poor prognostic features. Management of localized HL has shifted from radiation alone to combined modality strategies with brief courses of combination chemotherapy followed by involved-field radiation therapy. Patients with advanced stage disease receive a longer course of chemotherapy commonly without radiation therapy. Clinical trials are being conducted using the early interim response or response at the end of therapy as measured by PET scan to determine treatment.


NPC1L1 Deficiency Suppresses Ileal Fibroblast Growth Factor 15 Expression and Increases Bile Acid Pool Size in High-Fat-Diet-Fed Mice.
Niemann-Pick C1-like 1 (NPC1L1) mediates intestinal uptake of dietary and biliary cholesterol and is the target of ezetimibe, a cholesterol absorption inhibitor used to treat hypercholesterolemia. Genetic deletion of NPC1L1 or ezetimibe treatment protects mice from high-fat diet (HFD)-induced obesity; however, the molecular mechanisms responsible for this therapeutic benefit remain unknown. A major metabolic fate of cholesterol is its conversion to bile acids. We found that NPC1L1 knockout (L1-KO) mice fed an HFD had increased energy expenditure, bile acid pool size, and fecal bile acid excretion rates. The elevated bile acid pool in the HFD-fed L1-KO mice was enriched with tauro-β-muricholic acid. These changes in the L1-KO mice were associated with reduced ileal mRNA expression of fibroblast growth factor 15 (FGF15) and increased hepatic mRNA expression of cholesterol 7α-hydroxylase (Cyp7A1) and mitochondrial sterol 27-hydroxylase (Cyp27A1). In addition, mRNA expression of the membrane bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and type 2 iodothyronine deiodinase (Dio2) were elevated in brown adipose tissue of L1-KO mice, which is known to promote energy expenditure. Thus, altered bile acid homeostasis and signaling may play a role in protecting L1-KO mice against HFD-induced obesity.


Complete genome sequence of the halophile bacterium Kushneria marisflavi KCCM 80003T, isolated from seawater in Korea.
We present the genome sequence of Kushneria marisflavi KCCM 80003T isolated from Yellow Sea in Korea. The complete genome of KCCM 80003T consisted of a single, circular chromosome of 3,667,185bp, with an average G+C content of 59.05%, and 3287 coding sequences, 12 rRNAs, and 66 tRNAs. Kushneria marisflavi KCCM 80003T, belonging to the family Halomonadaceae, exhibited resistance to high salt concentrations and possessed potassium metabolism- or osmotic stress-related coding sequences, including potassium homeostasis, ectoine biosynthesis and regulation, choline and betaine uptake, and betaine biosynthesis features in the genome. These results provide a basis for understanding resistance strategies to osmotic stress at the genetic level and accordingly have implications for genetic engineering and biotechnology.


Effects of fluvastatin on plasma levels of low-density lipoprotein subfractions, oxidized low-density lipoprotein, and soluble adhesion molecules: a twenty-four-week, open-label, dose-increasing study.
Statins not only lower low-density lipoprotein (LDL) levels, but also have several antiarteriosclerotic effects (eg, decreasing arterial inflammation and arterial smooth muscle cell proliferation, as well as antioxidant effects). The relationship between the dose of statin and its effects on plasma LDL levels and other arteriosclerosis-related effects remains to be clarified. We investigated the effect of a statin, fluvastatin, on plasma levels of lipoprotein subfractions, oxidized LDL (Ox-LDL), Ox-LDL immunoglobulin G (IgG), soluble adhesion molecules, reverse cholesterol transport (ie, transport of esterified high-density lipoprotein cholesterol [HDL-C] to triglyceride [TG]-rich lipoproteins by cholesteryl ester transfer protein [CETP] and reduction of plasma HDL-C levels), and on the intima-medial thickness (IMT) of the common carotid arteries. Patients with nonfamilial type 2 hyperlipoproteinemia were eligible for this open-label, dose-increasing study. Fluvastatin 20 mg/d was administered for the first 12 weeks, and the daily dose was increased to 40 mg for the subsequent 12 weeks. Patients were examined at baseline and after 12 and 24 weeks of treatment. Plasma lipoprotein subfractions were determined using sequential ultracentrifugation at 100,000g. The plasma levels of Ox-LDL, Ox-LDL-IgG, CETP, and soluble adhesion molecules were measured using sandwich enzyme-linked immunosorbent assay. The maximum IMT of the common carotid arteries was measured using sonography. The plasma levels of LDL cholesterol (LDL-C) and apolipoprotein (apo) B were reduced by 25% and 17%, respectively (P<0.001 for both), after 12 weeks of treatment with fluvastatin 20 mg/d; no further significant reductions in LDL were observed after increasing the daily dose to 40 mg. Fluvastatin 20 mg/d for 12 weeks decreased plasma levels of intermediate-density lipoprotein cholesterol, LDL-I-C, LDL-II-C, and LDL-III-C by 25% (P<0.01), 30% (P<0.001), 23% (P<0.01), and 20% (P = 0.02), respectively. No further significant reductions in these levels were observed after increasing the daily dose to 40 mg. The plasma levels of Ox-LDL decreased in a similar fashion to the plasma levels of LDL-C (P<0.001). However, plasma levels of Ox-LDL-IgG and soluble P-selectin did not decrease after 12 weeks of fluvastatin 20 mg/d, but did decrease significantly (both 22%) after the next 12 weeks of treatment with fluvastatin 40 mg/d (P<0.05). Plasma levels of intercellular adhesion molecule 1and vascular cell adhesion molecule 1 and CETP mass were not altered by fluvastatin treatment. Significant changes in maximum IMT of the common carotid arteries were not seen throughout 24 weeks of fluvastatin treatment. In this patient population, fluvastatin 20 mg/d was sufficient to significantly reduce plasma levels of LDL, the 3 LDL subfractions, and Ox-LDL, but was not sufficient to reduce plasma levels of Ox-LDL-IgG and soluble P-selectin. It is important to check not only plasma lipoprotein levels but also other factors relating to arteriosclerosis during treatment with statins for the prevention and treatment of arteriosclerosis.


Therapeutic Characteristics, Chemotherapy-Related Toxicities and Survivorship in Colorectal Cancer Patients.
Colorectal Cancer (CRC) is a major health problem around the globe. In Morocco, the disease ranks third after breast and lung cancers. This study is the first in Morocco to investigate epidemiological, clinical and therapeutic features while exhaustively describing toxic side-effects to chemotherapy of CRC and studying the 3-years survivorship. This is a descriptive and analytical retrospective study of about 290 patients with CRC enrolled during the period of January-December 2013. Statistical analysis was performed to correlate clinicopathological data with chemotherapy toxicity and survivorship in patients, by Chi2 test. Overall Survival (OS) rate has been calculated by the Kaplan-Meier method and compared using Log-rank test. Fifty-five percent had a tumor localized in rectum, and 42,8% in colon. Mean age of these patients at diagnosis was 56,16 ± 14,6. incidence rate of adverse events (grade I to IV) was 85,6%. Diarrhea was the predominant toxicity (4.6%) occurring at a high grade (grade III-IV).The 3-years OS rate of patients with CRC was 71%. OS decreased by age, and patients with age subgroup between 40 to 59 years had a better OS than the other age subgroups (60 to 79 years and >80 years) with a p-value of 0.0001. Occurence of toxicity (all grades and types) was linked to a higher survival rates compared to the group who had no toxicity noticed (p-value of 0.001). Our study shows that patients who had a polychemotherapy had a better OS than those who had monotherapy (p-value of 0.002).


The impacts of coordinative exercise on executive function in kindergarten children: an ERP study.
This study examined the behavioral and neuroelectrical impacts of a coordinative exercise intervention with different exercise intensities on executive function in kindergarten children. Participants underwent the Eriksen flanker test before and after an exercise program that involved 35-min sessions twice per week for 8 weeks, with either low or moderate intensity. Our findings revealed that exercise intervention, regardless of intensity, resulted in shorter reaction times and higher response accuracy in both congruent and incongruent trials, with incongruent trials receiving a larger benefit from exercise compared with congruent trials. Additionally, neuroelectrical activation demonstrated greater P3 amplitude and shorter P3 latency following exercise in both trials. These results suggest that coordinative exercise may specifically benefit prefrontal-dependent tasks in the immature brain state of kindergarten children by increasing the allocation of attentional resources and enhancing the efficiency of neurocognitive processing.


Insulin pump therapy: a meta-analysis.
To conduct a meta-analysis of the metabolic and psychosocial impact of continuous subcutaneous insulin infusion (CSII) therapy on adults, adolescents, and children. Studies were identified and data regarding study design, year of publication, sample size, patient's age, diabetes duration, and duration of CSII therapy were collected. Means and SDs for glycohemoglobin, blood glucose, insulin dosages, and body weight for CSII and comparison conditions were subjected to meta-analytic procedures. Data regarding pump complications and psychosocial functioning were reviewed descriptively. A total of 52 studies, consisting of 1,547 patients, were included in the meta-analysis. Results indicate that CSII therapy is associated with significant improvements in glycemic control (decreased glycohemoglobin and mean blood glucose). A descriptive review of potential complications of CSII use (e.g., hypoglycemia, diabetic ketoacidosis [DKA], pump malfunction, and site infections) suggests a decreased frequency of hypoglycemic episodes but an increased frequency of DKA in studies published before 1993. CSII therapy is associated with improved glycemic control compared with traditional insulin therapies (conventional therapy and multiple daily injections) and does not appear to be associated with significant adverse outcomes. Additional studies are needed to further examine the relative risks of CSII therapy, including the potential psychosocial impact of this technologically advanced therapy.


Multiple preinvasive and invasive HPV-related lesions of the anogenital tract in a female patient with HIV infection: A case report.
Patients with human immunodeficiency virus (HIV) infection have been shown to be at increased risk for high-risk human papillomavirus (HR-HPV) infection of the anogenital tract. Furthermore, in the last decades, the introduction of highly active antiretroviral therapy (HAART) has increased the longevity of these patients who now live long enough to develop HPV-related cancers; hence, the impact of HPV infection on HIV-positive patients is of increasing concern. We reported the case of an HIV-positive female patient on HAART with a good virological and immunological response and with a long history of HPV-related intraepithelial and invasive lesions of the anogenital tract. From 1996 to 2016, this patient was diagnosed with a high grade cervical intraepithelial neoplasia; a HR-HPV positive inguinal lymph node metastasis from clinically undetectable primary squamous cell carcinoma; a HPV-related vulvar high-grade squamous intraepithelial lesion and an invasive squamous cell carcinoma of the anus. All the intraepithelial and invasive lesions detected were properly treated, and subsequent follow up visits with gynecologic examination, anoscopy, pap smear and anal cytology were performed. After a recurrence of the anal cancer and a subsequent salvage surgery with abdominoperineal resection, at the last available follow up visit no sign of disease recurrence was found. This case stresses the importance of an accurate multidisciplinary follow-up in HIV-positive patients, including not only the routine medical, immunological, and virological evaluation, but also a periodical complete examination of the anogenital tract with cervicovaginal and anal cytology, colposcopy, high resolution anoscopy, and vulvar examination.


Glioma expansion in collagen I matrices: analyzing collagen concentration-dependent growth and motility patterns.
We study the growth and invasion of glioblastoma multiforme (GBM) in three-dimensional collagen I matrices of varying collagen concentration. Phase-contrast microscopy studies of the entire GBM system show that invasiveness at early times is limited by available collagen fibers. At early times, high collagen concentration correlates with more effective invasion. Conversely, high collagen concentration correlates with inhibition in the growth of the central portion of GBM, the multicellular tumor spheroid. Analysis of confocal reflectance images of the collagen matrices quantifies how the collagen matrices differ as a function of concentration. Studying invasion on the length scale of individual invading cells with a combination of confocal and coherent anti-Stokes Raman scattering microscopy reveals that the invasive GBM cells rely heavily on cell-matrix interactions during invasion and remodeling.


Neuroendocrine responses to stimulation of the vagus nerves in bursts in conscious calves.
Effects of stimulation of the peripheral ends of the vagus nerves below the heart at 4 Hz continuously, and at 40 Hz for 1 s at 10 s intervals, have been compared in conscious calves below behavioural threshold. Neither pattern of stimulation caused any significant change in mean aortic blood pressure or heart rate but both invariably produced a substantial increase in the flow of intestinal lymph. Each form of stimulation provoked release of glucagon, insulin and pancreatic polypeptide from the pancreas and produced a small but significant rise in mean arterial plasma glucose concentration. The release of gastric inhibitory peptide- and bombesin-like molecules from the gastrointestinal tract was not affected by vagal stimulation whereas release of vasoactive intestinal peptide was observed in response to both patterns of vagal stimulation. Evidence was obtained to suggest that gastrin-like peptides are preferentially released into the bloodstream whereas cholecystokinin-like peptides are not. Vagal stimulation releases somatostatin from the gastrointestinal tract but discontinuous stimulation seems to inhibit the release of somatostatin into the general circulation. The results that have been obtained, employing this particular protocol, suggest that the pattern of the stimulus that is applied to the vagal splanchnic innervation has relatively little effect on neuroendocrine response in this species.


The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation.
Autoinflammatory diseases were first recognized nearly 20 years ago as distinct clinical and immunological entities caused by dysregulation in the innate immune system. Since then, advances in genomic techniques have led to the identification of new monogenic disorders and their corresponding signaling pathways. Here we review these monogenic autoinflammatory diseases, ranging from periodic fever syndromes caused by dysregulated inflammasome-mediated production of the cytokine IL-1β to disorders arising from perturbations in signaling by the transcription factor NF-κB, ubiquitination, cytokine signaling, protein folding, type I interferon production and complement activation, and we further examine their molecular mechanisms. We also explore the overlap among autoinflammation, autoimmunity and immunodeficiency, and pose a series of unanswered questions that are expected to be central in autoinflammatory disease research in the coming decade.


The evolving role of FLT3 inhibitors in acute myeloid leukemia: quizartinib and beyond.
Acute myeloid leukemia remains associated with poor outcomes despite advances in our understanding of the complicated molecular events driving leukemogenesis and malignant progression. Those patients harboring mutations in the FLT3 receptor tyrosine kinase have a particularly poor prognosis; however, significant excitement has been generated by the emergence of a variety of targeted inhibitors capable of suppressing FLT3 signaling in vivo. Here we will review results from preclinical studies and early clinical trials evaluating both first- and second-generation FLT3 inhibitors. Early FLT3 inhibitors (including sunitinib, midostaurin, and lestaurtinib) demonstrated significant promise in preclinical models of FLT3 mutant AML. Unfortunately, many of these compounds failed to achieve robust and sustained FLT3 inhibition in early clinical trials, at best resulting in only transient decreases in peripheral blast counts. These results have prompted the development of second-generation FLT3 inhibitors, epitomized by the novel agent quizartinib. These second-generation inhibitors have demonstrated enhanced FLT3 specificity and have been generally well tolerated in early clinical trials. Several FLT3 inhibitors have reached phase III clinical trials, and a variety of phase I/II trials exploring a role for these novel compounds in conjunction with conventional chemotherapy or hematopoietic stem cell transplantation are ongoing. Finally, molecular insights provided by FLT3 inhibitors have shed light upon the variety of mechanisms underlying the acquisition of resistance and have provided a rationale supporting the use of combinatorial regimens with other emerging targeted therapies.


Macroscopically Degenerate Exactly Solvable Point in the Spin-1/2 Kagome Quantum Antiferromagnet.
Frustrated quantum magnets are a central theme in condensed matter physics due to the richness of their phase diagrams. They support a panoply of phases including various ordered states and topological phases. Yet, this problem has defied a solution for a long time due to the lack of controlled approximations which make it difficult to distinguish between competing phases. Here we report the discovery of a special quantum macroscopically degenerate point in the XXZ model on the spin-1/2 kagome quantum antiferromagnet for the ratio of Ising to antiferromagnetic transverse coupling J_{z}/J=-1/2. This point is proximate to many competing phases explaining the source of the complexity of the phase diagram. We identify five phases near this point including both spin-liquid and broken-symmetry phases and give evidence that the kagome Heisenberg antiferromagnet is close to a transition between two phases.


Site-specific autonomic vasomotor responses and their interactions in rat gingiva.
Blood flow in the gingiva, comprising the interdental papilla as well as attached and marginal gingiva, is important for maintaining of gingival function and is modulated by risk factors such as stress that may lead to periodontal disease. Marked blood flow changes mediated by the autonomic (parasympathetic and sympathetic) nervous system may be essential for gingival hemodynamics. However, differences in autonomic vasomotor responses and their functional significance in different parts of the gingiva are unclear. We examined the differences in autonomic vasomotor responses and their interactions in the gingiva of anesthetized rats. Parasympathetic vasodilation evoked by the trigeminal (lingual nerve)-mediated reflex elicited frequency-dependent blood flow increases in gingivae, with the increases being greatest in the interdental papilla. Parasympathetic blood flow increases were significantly reduced by intravenous administration of the atropine and VIP antagonist. The blood flow increase evoked by acetylcholine administration was higher in the interdental papilla than in the attached gingiva, whereas that evoked by VIP agonist administration was greater in the attached gingiva than in the interdental papilla. Activation of the cervical sympathetic nerves decreased gingival blood flow and inhibited parasympathetically induced blood flow increases. Our results suggest that trigeminal-parasympathetic reflex vasodilation 1) is more involved in the regulation of blood flow in the interdental papilla than in the other parts of the gingiva, 2) is mediated by cholinergic (interdental papilla) and VIPergic systems (attached gingiva), and 3) is inhibited by excess sympathetic activity. These results suggest a role in the etiology of periodontal diseases during mental stress.


Extracellular vesicles in diagnosis and therapy of kidney diseases.
Extracellular vesicles (EV) are endogenously produced, membrane-bound vesicles that contain various molecules. Depending on their size and origins, EVs are classified into apoptotic bodies, microvesicles, and exosomes. A fundamental function of EVs is to mediate intercellular communication. In kidneys, recent research has begun to suggest a role of EVs, especially exosomes, in cell-cell communication by transferring proteins, mRNAs, and microRNAs to recipient cells as nanovectors. EVs may mediate the cross talk between various cell types within kidneys for the maintenance of tissue homeostasis. They may also mediate the cross talk between kidneys and other organs under physiological and pathological conditions. EVs have been implicated in the pathogenesis of both acute kidney injury and chronic kidney diseases, including renal fibrosis, end-stage renal disease, glomerular diseases, and diabetic nephropathy. The release of EVs with specific molecular contents into urine and plasma may be useful biomarkers for kidney disease. In addition, EVs produced by cultured cells may have therapeutic effects for these diseases. However, the role of EVs in kidney diseases is largely unclear, and the mechanism underlying EV production and secretion remains elusive. In this review, we introduce the basics of EVs and then analyze the present information about the involvement, diagnostic value, and therapeutic potential of EVs in major kidney diseases.


A prospective study of adolescent risk and protective factors for problem gambling among young adults.
There is a paucity of research examining prospective predictors of problem gambling. The current study utilised a large longitudinal data set (N = 2328) to examine a large range of adolescent risk and protective factors for problem gambling in young adulthood. These risk and protective factors covered the domains of the community, family, school, peer group and individual. Numerous predictors associated with the family, school and peer-individual were statistically significant in analyses adjusted for gender and age. However, in the fully adjusted multivariate analyses, only two predictors were statistically significant. Within this model, gender (female) was associated with a reduced risk of young adult problem gambling, while family rewards for prosocial involvement moderated the risk relationship between adolescent alcohol use and young adult problem gambling. These findings highlight the importance of adolescent alcohol use and family environment as potentially modifiable predictors of young adult problem gambling.


Associations between the dietary intake of antioxidant nutrients and the risk of hip fracture in elderly Chinese: a case-control study.
The role of oxidative stress in skeletal health is unclear. The present study investigated whether a high dietary intake of antioxidant nutrients (vitamins C and E, β-carotene, animal-derived vitamin A, retinol equivalents, Zn and Se) is associated with a reduced risk of hip fracture in elderly Chinese. This 1:1 matched case-control study involved 726 elderly Chinese with hip fracture and 726 control subjects, recruited between June 2009 and May 2013. Face-to-face interviews were conducted to determine habitual dietary intakes of the above-mentioned seven nutrients based on a seventy-nine-item FFQ and information on various covariates, and an antioxidant score was calculated. After adjustment for potential covariates, dose-dependent inverse associations were observed between the dietary intake of vitamin C, vitamin E, β-carotene, and Se and antioxidant score and the risk of hip fracture (P for trend ≤ 0·005). The OR of hip fracture for the highest (v. lowest) quartile of intake were 0·39 (95 % CI 0·28, 0·56) for vitamin C, 0·23 (95 % CI 0·16, 0·33) for vitamin E, 0·51 (95 % CI 0·36, 0·73) for β-carotene, 0·43 (95 % CI 0·26, 0·70) for Se and 0·24 (95 % CI 0·17, 0·36) for the antioxidant score. A moderate-to-high dietary intake of retinol equivalents in quartiles 2-4 (v. 1) was found to be associated with a lower risk of hip fracture (OR range: 0·51-0·63, P< 0·05). No significant association was observed between dietary Zn or animal-derived vitamin A intake and hip fracture risk (P for trend >0·20). In conclusion, a higher dietary intake of vitamins C and E, β-carotene, and Se and a moderate-to-high dietary intake of retinol equivalents are associated with a lower risk of hip fracture in elderly Chinese.


Bipolar technology for transurethral prostatectomy.
Bipolar electrosurgical technology has gained worldwide attention with various companies introducing devices, such as the Gyrus PlasmaKinetic™ Tissue Management System (Gyrus ACMI, MN, USA) and the Olympus(®) UES-40 Surgmaster generator (Olympus, Tokyo, Japan), which is aimed at minimizing the morbidity of standard monopolar transurethral resection of the prostate (TURP), whilst also maintaining efficacy and durability. The Gyrus PlasmaKinetic System effectively controls bleeding, resulting in a clear operative field; it greatly reduces risk of transurethral resection syndrome, thus providing a new option among minimally-invasive surgical treatments for benign prostatic hyperplasia. In a meta-analysis of head-to-head comparisons between the monopolar and bipolar TURP, the operation times, transfusion rates, retention rates after catheter removal and urethral complications did not differ significantly. Irrigation and catheterization duration was significantly longer with monopolar TURP.


Abnormalities in the awareness and control of action.
Much of the functioning of the motor system occurs without awareness. Nevertheless, we are aware of some aspects of the current state of the system and we can prepare and make movements in the imagination. These mental representations of the actual and possible states of the system are based on two sources: sensory signals from skin and muscles, and the stream of motor commands that have been issued to the system. Damage to the neural substrates of the motor system can lead to abnormalities in the awareness of action as well as defects in the control of action. We provide a framework for understanding how these various abnormalities of awareness can arise. Patients with phantom limbs or with anosognosia experience the illusion that they can move their limbs. We suggest that these representations of movement are based on streams of motor commands rather than sensory signals. Patients with utilization behaviour or with delusions of control can no longer properly link their intentions to their actions. In these cases the impairment lies in the representation of intended movements. The location of the neural damage associated with these disorders suggests that representations of the current and predicted state of the motor system are in parietal cortex, while representations of intended actions are found in prefrontal and premotor cortex.


The role of 3'UTR-protein complexes in the regulation of protein multifunctionality and subcellular localization.
Multifunctional proteins often perform their different functions when localized in different subcellular compartments. However, the mechanisms leading to their localization are largely unknown. Recently, 3'UTRs were found to regulate the cellular localization of newly synthesized proteins through the formation of 3'UTR-protein complexes. Here, we investigate the formation of 3'UTR-protein complexes involving multifunctional proteins by exploiting large-scale protein-protein and protein-RNA interaction networks. Focusing on 238 human 'extreme multifunctional' (EMF) proteins, we predicted 1411 3'UTR-protein complexes involving 54% of those proteins and evaluated their role in regulating protein cellular localization and multifunctionality. We find that EMF proteins lacking localization addressing signals, yet present at both the nucleus and cell surface, often form 3'UTR-protein complexes, and that the formation of these complexes could provide EMF proteins with the diversity of interaction partners necessary to their multifunctionality. Our findings are reinforced by archetypal moonlighting proteins predicted to form 3'UTR-protein complexes. Finally, the formation of 3'UTR-protein complexes that involves up to 17% of the proteins in the human protein-protein interaction network, may be a common and yet underestimated protein trafficking mechanism, particularly suited to regulate the localization of multifunctional proteins.


Non-convulsive febrile status epilepticus mimicking a postictal state after a febrile seizure: an ictal electroclinical and evolutive study.
Febrile status epilepticus evolves from a febrile seizure (FS) in 5% of cases. Its prompt recognition is challenging, especially when motor manifestations are absent or subtle. We describe the ictal electroclinical features of non-convulsive febrile status epilepticus (NCFSE) following an apparently concluded FS, initially misinterpreted as postictal obtundation and in some way mimicking the described "non-epileptic twilight state". We present an electroclinical study of 18 children, collected in our unit, who presented with NCFSE after an apparently resolved FS, longitudinally followed for one year to seven years and nine months (mean: four years and three months). The age at first NCFSE ranged between one year and two months and five years and eight months (mean: two years and six months). Patients were examined after spontaneous or rectal diazepam-induced resolution of a FS, while showing persisting impairment of awareness. A lack of responsiveness to painful stimulation, abnormal posturing and aphasia were present in all cases, variably associated with perioral cyanosis, hypersalivation, automatisms, gaze deviation and other lateralizing signs; eyes were open. The EEG recording started 20 to 140 minutes after the apparent resolution of the FS and was invariably characterized by delta or theta-delta pseudorhythmic activity, mainly involving the fronto-temporal regions, with hemispheric predominance in two thirds of the cases. The electroclinical condition, lasting 25 to 210 minutes, quickly recovered after intravenous diazepam. Follow-up revealed normal neurodevelopment and EEG in almost all patients (learning disability emerged in three). In five subjects, NCSE relapsed (twice in two). None presented afebrile seizures. Our series highlights the electroclinical features of focal NCFSE. Distinctive elements are a lack of reactivity, cyanosis, lateralizing clinical and EEG signs, and resolution clearly tied to intravenous benzodiazepine administration.


A systematic review on the transfer of information during nurse transitions in care.
To examine the qualitative evidence on dynamics of knowledge transfer during transitions in care in acute care hospitals. The most common transition between nurse care providers is the intershift handoff. As these handoffs tend to be time-consuming and costly, it is important to understand the dynamics of the transfer of information at this time and, by extension, improve quality and safety. Systematic Review. Qualitative studies conducted between 1988 and 2012 were sought. A comprehensive four-stage search strategy identified 125 qualitative studies that met the inclusion criteria. Of these, 50 were retrieved for appraisal. Retrieved papers were assessed by two independent reviewers for methodological quality prior to inclusion in the review using a standardised critical appraisal instrument. The final sample consisted of 29 qualitative studies. This represented more than 800 nursing handoffs and 300 nurse interviews. Sixteen categories were identified, which were then subjected to a meta-synthesis to produce a single comprehensive set of synthesised findings. The evidence shows the handoff to be a complex, social interaction highly sensitive to context and cultural norms, an activity essential to multiple functions that extend beyond quality and safety. They are subject to wide variability in both the methods used and the kind of information that is handed off. Notably, the elucidation of the different ways in which individual nurses act as gatekeepers and influence patient care is a major finding of this review. The results of this systemic review provide evidence that a consistent guideline may provide an optimal shift report given the findings of this review that information transferred may be random and variable, inconsistent and incongruent, inaccurate or absent.


Predicting life satisfaction of the Angolan elderly: a structural model.
Satisfaction with life is of particular interest in the study of old age well-being because it has arisen as an important component of old age. A considerable amount of research has been done to explain life satisfaction in the elderly, and there is growing empirical evidence on best predictors of life satisfaction. This research evaluates the predictive power of some aging process variables, on Angolan elderly people's life satisfaction, while including perceived health into the model. Data for this research come from a cross-sectional survey of elderly people living in the capital of Angola, Luanda. A total of 1003 Angolan elderly were surveyed on socio-demographic information, perceived health, active engagement, generativity, and life satisfaction. A Multiple Indicators Multiple Causes model was built to test variables' predictive power on life satisfaction. The estimated theoretical model fitted the data well. The main predictors were those related to active engagement with others. Perceived health also had a significant and positive effect on life satisfaction. Several processes together may predict life satisfaction in the elderly population of Angola, and the variance accounted for it is large enough to be considered relevant. The key factor associated to life satisfaction seems to be active engagement with others.


Robust, tunable biological oscillations from interlinked positive and negative feedback loops.
A simple negative feedback loop of interacting genes or proteins has the potential to generate sustained oscillations. However, many biological oscillators also have a positive feedback loop, raising the question of what advantages the extra loop imparts. Through computational studies, we show that it is generally difficult to adjust a negative feedback oscillator's frequency without compromising its amplitude, whereas with positive-plus-negative feedback, one can achieve a widely tunable frequency and near-constant amplitude. This tunability makes the latter design suitable for biological rhythms like heartbeats and cell cycles that need to provide a constant output over a range of frequencies. Positive-plus-negative oscillators also appear to be more robust and easier to evolve, rationalizing why they are found in contexts where an adjustable frequency is unimportant.


[Computer or conventional tomography? Comparative studies in craniofacial fractures].
Both conventional tomography and computed tomography are usefully employed in examinations of facial and frontal skull base fractures. Whereas computed tomography offers an excellent high-resolution image, conventional tomography yields a better spatial representation. The advantages and limitations of these techniques in the diagnosis of facial and frontal skull base fractures are presented and discussed.


A Boron-Dependent Antibiotic Derived from a Calcium-Dependent Antibiotic.
The prevalence of drug-resistant bacterial pathogens foreshadows a healthcare crisis. Calcium-dependent antibiotics (CDAs) are promising candidates to combat infectious diseases as many of them show mechanisms of action (MOA) orthogonal to widespread resistance mechanisms. The calcium dependence is nonetheless one of the hurdles toward realizing their full potential. Using laspartomycin C (LspC) as a model, we explored the possibility of reducing, or even eliminating, its calcium dependence. We report herein a synthetic LspC analog (B1) whose activity no longer depended on calcium and is instead induced by phenylboronic acid (PBA). In LspC, Asp1 and Asp7 coordinate to calcium to anchor itself in the active conformation; these residues are replaced by serine in B1 and condense with PBA to form a boronic ester with the same anchoring effect. Using thin-layer chromatography, MS, NMR, and complementation assays, we demonstrated that B1 inhibits bacterial growth via the same MOA as LspC, i.e., sequestering the cell wall biosynthetic intermediate undecaprenyl phosphate. B1 is as potent and effective as LspC against several Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. Our success in converting a CDA to a boron-dependent antibiotic opens a new avenue in the design and functional control of drug molecules.


Polymorphous ZnO complex architectures: selective synthesis, mechanism, surface area and Zn-polar plane-codetermining antibacterial activity.
Complex ZnO architectures with tunable morphologies and structures were obtained by modulating only the base type and molar ratio of base to Zn2+ (α) using an easy one-pot hydrothermal approach without any template or organic additive. Characterizations by X-ray diffraction, Fourier-transform infrared spectrometry, scanning electron microscopy, transmission electron microscopy, and surface area analysis were performed. The effect of the base type and base/Zn2+ molar ratio on the morphology and corresponding mechanism were determined. The correlations between the microstructure and properties were established. The antibacterial effect of the ZnO samples was probably due to a combination of variable factors. Better antibacterial activity is derived from more effective antibacterial surfaces, which are mainly associated with the specific surface area and Zn-polar plane. Thus, flower-like architectures with larger specific surface areas and more highly exposed (0001) Zn-polar surfaces outwards are promising structures for ZnO antibacterial agents. This work provides a guide for devising and synthesizing highly efficient antibacterial materials.


[Problems occurring in the application of cytogenetic biomarkers for alcoholics with and without malignant diseases].
Applicability of alcohol- and smoking-related cancer-risk biomarkers might be modified by several factors. Among those, reality of self-reports on alcohol consumption of alcoholic patients with different diseases and extreme high mutagen hypersensitivity of Hungarians, as well as the immunologic role of peripheral lymphocytes as experimental objects of cytogenetic biomarkers seem to be new viewpoints of interest. To clarify these problems, 432 head and neck cancer patients (HNCP), 62 alcoholics with alcoholic hepatitis (ALCL), and 101 disease-free chronic alcoholics (ALC) were examined. Despite clinically confirmed alcohol-related diagnoses (and GGT and MCV values) only about half of HNCPs and ALCLs reported about any alcohol consumption, in contrast to the realistic self-reports of ALCs. In cytogenetic case control investigations no difference between the spontaneous rate of chromosomal aberrations (CAs) of healthy controls and ALCs was found, however, genetic instability expressed as a 40-50% elevation rate of CAs in HNCPs and ALCLs might be associated with systemic inflammatory reaction of lymphocytes. Bleomycin sensitivity assay showed the highest break/cell (b/c) values not in HNCPs (1.06 b/c) as it was reported earlier, but in "healthy" ALCs (1.52 b/c). This phenomenon can be related to the local effect of genotoxins (alcohol, smoking, and in particular the diet), which probably reflects merely a reaction of mucosal immune system. Nearly 50% of mutagen-hypersensitive Hungarian controls, in contrary to the expected 10-20% ones, might also be explained by this. Similarly, HNCPs with oral cancer, where the local mutagen effect was the most intensive, had the highest b/c values. In conclusion, when cytogenetic biomarkers of alcoholism are examined, the subjective character of self-reports at epidemiologic level and immunologic role of lymphocyte subpopulations as genetic confounders must also be taken into consideration.


Adipocytes fuel gastric cancer omental metastasis via PITPNC1-mediated fatty acid metabolic reprogramming.
Omental metastasis occurs frequently in gastric cancer (GC) and is considered one of the major causes of gastric cancer-related mortality. Recent research indicated that omental adipocytes might mediate this metastatic predilection. Phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) was identified to have a crucial role in metastasis. However, whether PITPNC1 participates in the interaction between adipocytes and GC omental metastasis is unclear. Methods: We profiled and analyzed the expression of PITPNC1 through analysis of the TCGA database as well as immunohistochemistry staining using matched GC tissues, adjacent normal gastric mucosa tissues (ANTs), and omental metastatic tissues. The regulation of PITPNC1 by adipocytes was explored by co-culture systems. By using both PITPNC1 overexpression and silencing methods, the role of PITPNC1 in anoikis resistance and metastasis was determined through in vitro and in vivo experiments. Results: PITPNC1 was expressed at higher rates in GC tissues than in ANTs; notably, it was higher in omental metastatic lesions. Elevated expression of PITPNC1 predicted higher rates of omental metastasis and a poor prognosis. PITPNC1 promoted anoikis resistance through fatty acid metabolism by upregulating CD36 and CPT1B expression. Further, PITPNC1 was elevated by adipocytes and facilitated GC omental metastasis. Lastly, in vivo studies showed that PITPNC1 was a therapeutic indicator of fatty acid oxidation (FAO) inhibition. Conclusion: Elevated expression of PITPNC1 in GC is correlated with an advanced clinical stage and a poor prognosis. PITPNC1 promotes anoikis resistance through enhanced FAO, which is regulated by omental adipocytes and consequently facilitates GC omental metastasis. Targeting PITPNC1 might present a promising strategy to treat omental metastasis.


Antiretroviral compounds: mechanisms underlying failure of HAART to eradicate HIV-1.
During the past decade, combined highly active antiretroviral therapy (HAART) consisting of the nucleoside, non-nucleoside and protease inhibitors has improved the outlook for HIV-infected individuals. However, despite the clinical improvement associated with HAART, current antiviral drug regimens are not able to eradicate HIV due to the persistence of virus in cellular reservoirs (predominantly long-lived memory CD4+ T cells and cells of the macrophage lineage) and anatomical sanctuary sites (brain and possibly testis). Detailed knowledge of viral reservoirs is essential for the effective design of therapeutic eradication strategies such as immunostimulation of virus-persistent reservoirs and better penetration of antiretroviral drugs into sanctuary sites. The recent therapeutic approaches undertaken thus far, including immune activation, intensification protocols combined with HAART, antiretroviral treatment during seroconversion, structured treatment interruptions, activation of latent infection or targeted killing of viral reservoirs have failed to completely eradicate the virus. This review provides an evaluation of the current HAART regimens exploring the reasons for their inability to eradicate HIV from cellular reservoirs and anatomical sanctuary sites. We also provide examples of therapeutic strategies that aim to eradicate the virus, flush out reservoirs and increase antiretroviral drug concentration in these cells and tissue compartments.


Facial expression recognition and emotional regulation in narcolepsy with cataplexy.
Cataplexy is pathognomonic of narcolepsy with cataplexy, and defined by a transient loss of muscle tone triggered by strong emotions. Recent researches suggest abnormal amygdala function in narcolepsy with cataplexy. Emotion treatment and emotional regulation strategies are complex functions involving cortical and limbic structures, like the amygdala. As the amygdala has been shown to play a role in facial emotion recognition, we tested the hypothesis that patients with narcolepsy with cataplexy would have impaired recognition of facial emotional expressions compared with patients affected with central hypersomnia without cataplexy and healthy controls. We also aimed to determine whether cataplexy modulates emotional regulation strategies. Emotional intensity, arousal and valence ratings on Ekman faces displaying happiness, surprise, fear, anger, disgust, sadness and neutral expressions of 21 drug-free patients with narcolepsy with cataplexy were compared with 23 drug-free sex-, age- and intellectual level-matched adult patients with hypersomnia without cataplexy and 21 healthy controls. All participants underwent polysomnography recording and multiple sleep latency tests, and completed depression, anxiety and emotional regulation questionnaires. Performance of patients with narcolepsy with cataplexy did not differ from patients with hypersomnia without cataplexy or healthy controls on both intensity rating of each emotion on its prototypical label and mean ratings for valence and arousal. Moreover, patients with narcolepsy with cataplexy did not use different emotional regulation strategies. The level of depressive and anxious symptoms in narcolepsy with cataplexy did not differ from the other groups. Our results demonstrate that narcolepsy with cataplexy accurately perceives and discriminates facial emotions, and regulates emotions normally. The absence of alteration of perceived affective valence remains a major clinical interest in narcolepsy with cataplexy, and it supports the argument for optimal behaviour and social functioning in narcolepsy with cataplexy.


Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1-mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Phloretin (PH) possesses anticancer, antitumor, and hepatoprotective effects, however, the effects and potential mechanisms of phloretin remain elusive. Five HCC cells were tested in vitro for sensitivity to PH, Sorafenib (Sor) or both and the apoptosis, signal transduction and phosphatase activity were analyzed. To validate the role of SHP-1, we used PTP inhibitor III and SHP-1 siRNA. Further, we used purified SHP-1 proteins or HCC cells expressing deletion N-SH2 domain or D61A point mutants to study the PH efficacy on SHP-1. The `in vivo studies were conducted using HepG2 and SK-Hep1 and Sor resistant HepG2SR and Huh7SR xenografts. Molecular docking was done with Swiss dock and Auto Dock Vina. PH inhibited cell growth and induced apoptosis in all HCC cells by upregulating SHP-1 expression and downregulating STAT3 expression and further inhibited pAKT/pERK signaling. PH activated SHP-1 by disruption of autoinhibition of SHP-1, leading to reduced p-STAT3Tyr705 level. PH induced apoptosis in two Sor-resistant cell lines and overcome STAT3, AKT, MAPK and VEGFR2 dependent Sor resistance in HCCs. PH potently inhibited tumor growth in both Sor-sensitive and Sor-resistant xenografts in vivo by impairing angiogenesis, cell proliferation and inducing apoptosis via targeting the SHP-1/STAT3 signaling pathway. Our data suggest that PH inhibits STAT3 activity in Sor-sensitive and -resistant HCCs via SHP-1-mediated inhibition of STAT3 and AKT/mTOR/JAK2/VEGFR2 pathway. Our results clearly indicate that PH may be a potent reagent for hepatocellular carcinoma and a noveltargeted therapy for further clinical investigations.


Nitric oxide increases leukocyte granule release during simulated extracorporeal circulation.
Nitric Oxide (NO) is reported to possess anti-inflammatory properties. The aim of this study was to investigate if nitric oxide affects leukocyte response during simulated extracorporeal circulation (SECC). Human blood was circulated for 23 hours through SECC circuit. Control group C (n = 5) was ventilated with an oxygen/air mixture, and NO was added in the study group (n = 5). Leukocyte response was determined by release of myeloperoxidase (MPO) and human neutrophil lipocalin (HNL) and by oxygen free radical production, estimated using chemiluminescence. Addition of NO significantly increased MPO at 30 minutes and 120 minutes of SECC and HNL at 120 minutes of SECC. Oxygen free radical production in whole blood was generally not affected by NO. Similarly, no significant differences were observed between the groups with regard to the chemiluminescence in isolated granulocytes. Nitric oxide increased release of leukocyte granule derived proteins; MPO and HNL at an early stage of simulated extracorporeal circulation. At the same time, nitric oxide did not affect the whole blood and leukocyte capacity to produce oxygen free radicals.


Complications of endoscopic ultrasonography.
Since its development in the 1980s, endoscopic ultrasonography (EUS) has undergone a great deal of technological modifications. EUS has become an important tool in the evaluation of patients with various clinical disorders and is increasingly being utilized in many centers. EUS has been evolving over the years; EUS-guided fine needle aspiration (FNA) for cytological and/or histological diagnosis has become standard practice and a wide array of interventional and therapeutic procedures are performed under EUS guidance for diseases which otherwise would have needed surgery, with its associated morbidities. EUS shares the risks and complications of other endoscopic procedures. This article addresses the specific adverse effects and risks associated with EUS, EUS-FNA and interventional EUS, namely perforation, bleeding, pancreatitis and infection. Measures to help minimizing these risks will also be discussed.


Treatment of premature labor with subcutaneous terbutaline.
Terbutaline was administered subcutaneously to treat premature labor for several years. As ritodrine has been approved by the Food and Drug Administration for this purpose, the authors considered it necessary to determine the efficacy of their terbutaline protocol. The hospital records were reviewed for all patients treated for premature labor with subcutaneous and oral terbutaline sulfate during a recent 4-month period. The regimen was highly effective in prolonging pregnancy for the 44 patients with intact fetal membranes, 88.6% of whom delivered 72 hours or more after start of therapy and 79.5% of whom had delivery delayed by 1 week or more. These results are comparable with those reported for intravenous administration of terbutaline or ritodrine hydrochloride. Efficacy was much less among the 19 patients in whom terbutaline was used to delay delivery after labor with premature rupture of the membranes. Of this group, 52.6% had delivery delayed to 72 hours or more, but only 10.5% had a delay of 1 week or more. Maternal side effects and neonatal complications were minimal. Successful tocolysis with beta2-sympathomimetic drugs appears to be possible without the need for intravenous therapy and at lower doses than customarily used.


Virtual neuroendoscopy, a comparative magnetic resonance and anatomical study.
We evaluated the usefulness and reliability of intraventricular virtual neuroendoscopy based on a comparative anatomical study. Virtual intraventricular endoscopic images were calculated from 3D magnetic resonance images in five anatomic specimens. Contiguous 1.2 mm slices of the specimen heads were acquired at a 1.5 T MR scanner using a 3D-gradient echo sequence. The images were then transferred to an independent 3D-workstation (Sun Spark 20). After scanning the specimen heads, real endoscopy within the cerebral ventricles of these brains was performed with a standard rod lens system. Comparison between real and virtual endoscopic views of the intraventricular topography was based on the same anatomical reference and landmarks. Acquisition of MR data and virtual image post-processing have been possible in all specimens. The virtual endoscopic images of the ventricles were comparable to the intraventricular views obtained by a standard rod lens system. Virtual intraventricular neuroendoscopy can be employed for planning and simulating neuroendoscopic procedures. It enables the neurosurgeon to simulate the endoscopic procedure within the cerebral ventricles on the basis of the patient's individual anatomy prior to surgery.


Sexual Difficulties after Pelvic Radiotherapy: Improving Clinical Management.
Modern multimodality cancer treatment has led to more than 2 million people living with and beyond cancer in the UK, an impressive survival statistic on which clinicians and services continue to build. However, what is less readily acknowledged by health professionals and patients alike are the 500,000 people whose daily lives are adversely affected by the longer term consequences of cancer treatment. Macmillan Cancer Support estimate as many as 350,000 people in the UK experience sexual consequences of cancer and its treatment, an aspect of survivorship and rehabilitation that receives relatively scant attention in service provision, policy development and research terms. This overview addresses the sexual impact of radical pelvic radiotherapy for the more common (prostate, ano-rectal, cervical and endometrial) adult malignancies. Through discussion of the clinical assessment and management of desire, arousal, orgasmic and sexual pain difficulties that arise after pelvic radiotherapy, this overview offers an integrated biopsychosocial model of practice that incorporates the physical, psychological and relationship elements of these treatment sequelae. It is important that clinicians raise the profile of the sexual consequences of cancer treatment as a legitimate aspect of survivorship and service provision. Only in this way can the identification and management of treatment-induced sexual difficulties, frequently experienced by patients and their partners, be better understood and managed. Increased focus on the sexual consequences of treatment and cancer survivorship more broadly may, in time, lead to greater clinical recognition, service development and, most importantly, increased research devoted to the effective management of what remains a neglected aspect of cancer care.


Cultural Aspects of End-of-Life Advance Care Planning for African Americans: An Ethnonursing Study.
Advance directive completion rates among the general population are low, with even lower completion rates among African Americans (AAs). This study's purpose was to identify culturally based meanings, expressions, and traditions of end-of-life (EOL) advance care planning (ACP) and decision making in order to promote culturally congruent nursing care among African Americans. Leininger's Culture Care Theory and Ethnonursing Research Method guided the study. A convenience sample of 21 informants were interviewed in community settings. Data analysis was guided using Leininger's phases of ethnonursing data analysis for qualitative data. Three themes emerged that affect EOL decision making: (a) faith in God and belief in life after death, (b) a strong matriarchal family structure, and (c) fear of talking about death and mistrust of the U.S. health care system. AA culture, beliefs, and traditions influence EOL ACP and practices, and must be considered while providing culturally congruent care.


Effects of Eugenol on Pain Response to the Formalin Test and Plasma Antioxidant Activity in High Fructose Drinking Water in Male Rats.
Increased consumption of fructose in recent years has increased the risk of developing metabolic syndrome. In this syndrome, induction of oxidative stress, cellular dysfunction, and decrease of antioxidant capacity can change response to pain. Therefore, this study aims to investigate the antinociceptive and antioxidant effects of eugenol on metabolic syndrome induced by a fructose-rich diet in rats. The rats were randomly assigned to five groups, to be under experiment for eight weeks. The first, control group, the second fructose 10% plus tween 0.5% (Fr + veh), the third fructose 10% (Fr), and the fourth fructose 10% plus a single dose of eugenol 100 mg/kg (Fr + EoS). However, the fifth obtained fructose 10% plus a continuous dose of eugenol 20 mg/kg/day (Fr + EoC) for the last 10 days of the experiment. After formalin test, blood samples were taken from the animals' hearts followed by analysis for biochemical factors. This study shows that fructose administration does not change any pain response and there are not any changes in pain response between Fr group and control group. However, treatment with single and continuous dose of eugenol in Fr + EoS and Fr + EoC groups significantly decreases response to pain in the first and second phase of formalin test in comparison with Fr group (P<0.05). Continuous does of eugenol improved serum malondialdehyde and total antioxidant capacity levels in Fr + Eoc group in comparison with Fr group. In the present work, new findings suggest the beneficial effects of eugenol in pain relief, improved serum glucose, insulin levels, and improved antioxidant activity in metabolic syndrome.


A critical appraisal of the value of immunohistochemistry in diagnosis of uterine neoplasms.
In recent years there have been a plethora of publications regarding the value of immunohistochemical studies in diagnosis in gynecological pathology. In many instances, papers are published initially that suggest that a certain antibody or panel of antibodies is of value in the diagnosis of a particular neoplasm and in the distinction of this from mimics. However, this is usually quickly followed by other studies that somewhat contradict these findings. The aim of this review is to present a critical appraisal of the value of immunohistochemical studies in the diagnosis of uterine neoplasms with emphasis on the recent literature. It is stressed that immunohistochemistry is necessary in relatively few cases and a knowledge of the potential immunoreactivity of utilized antibodies is required. With regard to endometrial carcinoma, topics discussed in this review include antibodies of value in the distinction between type 1 and type 2 carcinoma, in the characterization of focal serous proliferations in endometrial polyps and non-polypoid endometrium, in the sometimes problematic distinction between an endometrial and an endocervical adenocarcinoma, and in the distinction between a uterine and ovarian serous carcinoma. The value of CD10 as a proposed marker of mesonephric adenocarcinoma is also discussed. With regard to uterine mesenchymal neoplasms, a critical appraisal of the value of relatively new antibodies, including CD10 and h-caldesmon, in distinguishing between a smooth muscle and an endometrial stromal neoplasm is discussed as is the immunophenotype of two rare uterine mesenchymal neoplasms, uterine tumor resembling ovarian sex cord tumor (UTROSCT) and perivascular epithelioid cell tumor (PEComa).


Lipid and fatty acid composition of cytoplasmic membranes from Streptomyces hygroscopicus and its stable protoplast-type L form.
The cells of an L-form strain of Streptomyces hygroscopicus have been grown for 20 years without a cell wall. Their cytoplasmic membranes have high stability and an unusual structural polymorphism. To clarify the importance of the lipid components for these membrane properties, a comparative analysis has been carried out with purified membranes of L-form cells, of parent vegetative hyphal cells (N-form cells), and of protoplasts derived from the latter. The phospholipid classes and fatty acids were determined by thin-layer chromatography (TLC), two-dimensional TLC, high-performance liquid chromatography, gas chromatography, and mass spectrometry. The qualitative compositions of cardiolipin (CL), lyso-cardiolipin (LCL), phosphatidylethanolamine (PE1 and PE2), lyso-phosphatidylethanolamine (LPE), phosphatidylinositolmannoside (PIM), phosphatidic acid (PA), dilyso-cardiolipin-phosphatidylinositol (DLCL-PI), and the 13 main fatty acids were the same in the three membrane types. However, significant quantitative differences were observed in the L-form membrane. They consist of a three- to fourfold-higher content of total, extractable lipids, 20% more phospholipids, an increased content of CL and PIM, and a reduced amount of the component DLCL-PI. Furthermore, the L-form membrane is characterized by a higher content of branched anteiso 15:0 and anteiso 17:0 fatty acids compared to that of the membranes of the walled vegetative cells. These fatty acids have lower melting points than their straight and iso-branched counterparts and make the membrane more fluid. The phospholipid composition of the protoplast membrane differs quantitatively from that of the N form and the L form. Whereas the phospholipid classes are mostly similar to that of the N form, the fatty acid pattern tends to be closer to that of the L-form membrane. The membranes of both the L-form cells and the protoplasts need to be more fluid because of their spherical cell shape and higher degree of curvature compared with N-form membranes.


Viral Diversity and Its Relationship With Environmental Factors at the Surface and Deep Sea of Prydz Bay, Antarctica.
A viral metagenomic analysis of five surface and two bottom water (878 meters below surface, mbs, and 3,357 mbs) samples from Prydz Bay, was conducted during February-March 2015. The results demonstrated that most of the DNA viruses were dsDNA viruses (79.73-94.06%, except at PBI1, 37.51%). Of these, Caudovirales (Siphoviridae, Myoviridae, and Podoviridae) phages were most abundant in surface seawater (67.67-71.99%), while nucleocytoplasmic large DNA viruses (NCLDVs) (Phycodnaviridae, Mimiviridae, and Pandoraviridae accounted for >30% of dsDNA viruses) were most abundant in the bottom water (3,357 mbs). Of the ssDNA viruses, Microviridae was the dominant family in PBI2, PBI3, PBOs, and PBI4b (57.09-87.55%), while Inoviridae (58.16%) was the dominant family in PBI1. Cellulophaga phages (phi38:1 and phi10:1) and Flavobacterium phage 11b, infecting the possible host strains affiliated with the family Flavobacteriaceae of the phylum Bacteroidetes, were abundant in surface water dsDNA viromes. The long contig (PBI2_1_C) from the viral metagenomes were most similar to the genome architectures of Cellulophaga phage phi10:1 and Flavobacterium phage 11b from the Arctic Ocean. Comparative analysis showed that the surface viral community of Prydz Bay could be clearly separated from other marine and freshwater environments. The deep sea viral community was similar to the deep sea viral metagenome at A Long-term Oligotrophic Habitat Assessment Station (ALOHA, at 22°45'N, 158°00'W). The multivariable analysis indicated that nutrients probably played an important role in shaping the local viral community structure. This study revealed the preliminary characteristics of the viral community in Prydz Bay, from both the surface and the deep sea. It provided evidence of the relationships between the virome and the environment in Prydz Bay and provided the first data from the deep sea viral community of the Southern Ocean.


Type 2 diabetes remission trajectories and variation in risk of diabetes complications: A population-based cohort study.
Biochemical remission of type 2 diabetes is achievable through dietary changes, physical activity and subsequent weight loss. We aim to identify distinct diabetes remission trajectories in a large population-based cohort over seven-years follow-up and to examine associations between remission trajectories and diabetes complications. Group-based trajectory modelling examined longitudinal patterns of HbA1c level (adjusting for remission status) over time. Multivariable Cox models quantified the association between each remission trajectory and microvascular complications, macrovascular complications, cardiovascular (CVD) events and all-cause mortality. Four groups were assigned. Group 1 (8,112 [13.5%]; achieving HbA1c <48 mmol/mol (6.5%) followed by increasing HbA1c levels); Group 2 (6,369 [10.6%]; decreasing HbA1c levels >48 mmol/mol (6.5%)); Group 3 (36,557 [60.6%]; stable high HbA1c levels); Group 4 (9,249 [15.3%]; stable low HbA1c levels (<48mmol/mol or <6.5%)). Compared to Group 3, Groups 1 and 4 had lower risk of microvascular complications (aHRs (95% CI): 0.65 (0.61-0.70), p-value <0.001;0.59 (0.55-0.64) p-value<0.001, respectively)), macrovascular complications (aHRs (95% CI): 0.83 (0.75-0.92), p-value<0.001; 0.66 (0.61-0.71), p-value<0.001) and CVD events (aHRs (95% CI): 0.74(0.67-0.83), p-value<0.001; 0.67(0.61-0.73), p-vlaue<0.001). Risk of CVD outcomes were similar for Groups 2 and 3. Compared to Group 3, Group 1 (aHR: 0.82(95% CI: 0.76-0.89)) had lower risk of mortality, but Group 4 had higher risk of mortality (aHR: 1.11(95% CI: 1.03-1.19)). Risk of CVD outcomes vary by pattern of remission over time, with lowest risk for those in remission longer. People who achieve remission, even for shorter periods of time, continue to benefit from this lower exposure to hyperglycaemia, which may, in turn, lower the risk of CVD outcomes including mortality.


The effect of minocycline, doxycycline and oxytetracycline on experimental mouse toxoplasmosis.
This is a comparative study of the effect of oral and parenteral administration of oxytetracycline, doxycycline and minocycline on experimental acute toxoplasmosis in mice. Two different inocula were used. All the antibiotics were ineffective orally. Doxycycline and minocycline were effective intraperitoneally, curing 90% of the mice who received the smaller inoculum. However, cerebral cysts of T. gondii were more common in the survivors treated with doxycycline.


Biomechanics and pathomechanisms of osteoarthritis.
Today, the most frequent chronic musculoskeletal disorder and the leading cause of disability in the elderly is osteoarthritis (OA). Approximately 43 million people in the United States and 15% of the world population are affected. Due to demographic changes, the incidence of OA is rapidly increasing, leading to an ascending socioeconomical and personal burden. Despite the exact cause of OA remains unknown, the pathogenic role of biomechanical dysfunction in OA is well established. For weight-bearing joints altered loading mechanisms, increased mechanical forces and changed biomechanics are significant contributing factors for initiation and progression of OA. Thus, OA is a disease of the whole joint, including muscles, tendons, ligaments, synovium and bone. This review focuses on the influence of biomechanics on the pathogenesis and progression of OA. We notably illustrate the pathological bioreactivity of soft tissues, subchondral bone and joint inflammation. Procedures, conservative or surgical, which actively alter the biomechanics of the lower limb, are promising strategies to treat symptoms as well as to influence disease progression in OA.


Incisional hernia in the elderly: risk factors and clinical considerations.
Ventral incisional hernia is a common complication of abdominal surgery. The marked improvements in medical technology and healthcare, lead to an increasing number of elderly patients to take advantage of even complex surgical procedures. The objective of this literature review was to analyze the risk factors for ventral incisional hernia in elderly patients and to identify measures that might decrease the incidence of this complication. An analysis of the surgical literature was performed using the search engines EMBASE, Cochrane Library, and PubMed with particular reference to elderly patients using the keywords: abdominal hernia, wound dehiscence, incisional hernia, incidence, trocar site hernia, and hernia prevention. In our opinion the risk factors for incisional hernia should be separately considered. First those related to the patients and to the abdominal surgery and, in addition, those related to the surgery of the abdominal wall defects. Reparative surgery of the abdominal wall, to date uniquely characterized by the use of the mesh, should be considered an additional risk factor for the occurrence of incisional hernia. However, the low incarceration risk, the risk of recurrence, the relevant rate of postoperative pain and discomfort and complications associated with mesh repair, as small bowel obstruction, mesh infection, and entero-cutaneous fistula, suggest that the general indication for surgical treatment of incisional hernias, in a symptomatic or oligosymptomatic elderly patients, should be critically reconsidered in order to avoid unnecessary surgery.


Effects of Propranolol on Bone, White Adipose Tissue, and Bone Marrow Adipose Tissue in Mice Housed at Room Temperature or Thermoneutral Temperature.
Growing female mice housed at room temperature (22°C) weigh the same but differ in body composition compared to mice housed at thermoneutrality (32°C). Specifically, mice housed at room temperature have lower levels of white adipose tissue (WAT). Additionally, bone marrow adipose tissue (bMAT) and cancellous bone volume fraction in distal femur metaphysis are lower in room temperature-housed mice. The metabolic changes induced by sub-thermoneutral housing are associated with lower leptin levels in serum and higher levels of Ucp1 gene expression in brown adipose tissue. Although the precise mechanisms mediating adaptation to sub-thermoneutral temperature stress remain to be elucidated, there is evidence that increased sympathetic nervous system activity acting via β-adrenergic receptors plays an important role. We therefore evaluated the effect of the non-specific β-blocker propranolol (primarily β1 and β2 antagonist) on body composition, femur microarchitecture, and bMAT in growing female C57BL/6 mice housed at either room temperature or thermoneutral temperature. As anticipated, cancellous bone volume fraction, WAT and bMAT were lower in mice housed at room temperature. Propranolol had small but significant effects on bone microarchitecture (increased trabecular number and decreased trabecular spacing), but did not attenuate premature bone loss induced by room temperature housing. In contrast, propranolol treatment prevented housing temperature-associated differences in WAT and bMAT. To gain additional insight, we evaluated a panel of genes in tibia, using an adipogenesis PCR array. Housing temperature and treatment with propranolol had exclusive as well as shared effects on gene expression. Of particular interest was the finding that room temperature housing reduced, whereas propranolol increased, expression of the gene for acetyl-CoA carboxylase (Acacb), the rate-limiting step for fatty acid synthesis and a key regulator of β-oxidation. Taken together, these findings provide evidence that increased activation of β1 and/or β2 receptors contributes to reduced bMAT by regulating adipocyte metabolism, but that this pathway is unlikely to be responsible for premature cancellous bone loss in room temperature-housed mice.


Mexoryl SX protects against solar-simulated UVR-induced photocarcinogenesis in mice.
The aim of this study was to determine, for regulatory purposes, the potential of Mexoryl SX, a broad UVA absorber that also absorbs to some extent in the UVB, to modify the UV radiation (UVR)-induced murine skin tumor development and growth. Skh-hr1 mice were exposed to solar-simulated UVR 5 days per week for 40 weeks. Two control groups were irradiated without topical application, three groups received a sunscreen preparation containing either the UVA absorber, Mexoryl SX at 5 or 10% concentration, or a filter that absorbs principally in the UVB, 2-ethylhexyl-p-methoxycinnamate (2-EHMC) at 5% concentration, introduced as a comparator test article. Sunscreen application was performed before UVR exposure 3 days per week and after UVR exposure on the other 2 days (consistent with the design of a standard photocarcinogenesis safety test). Two different weekly UVR doses were administrated: the lower dose was given to one group of unprotected animals, whereas the higher dose was administrated to the other unprotected group and to the three sunscreen-treated groups. The two UVR control groups demonstrated a UVR-dependent response for cumulative tumor prevalence, tumor yield and median latent period. Neither concentration of Mexoryl SX increased the probability of tumor development; consistent with the principles for safety testing, this provides evidence in that it is safe for use in sunlight. Although this study was explicitly designed as a safety test, the results also provide some clues about the efficacy of Mexoryl SX in decreasing the probability of tumor development. Topical administration of Mexoryl SX, at both concentrations, resulted in a 6 week delay in the median latent period compared to high UVR controls, whereas 5% 2-EHMC delayed the median latent periods only by 2 weeks. Tumor prevalence and yield show the same efficacy differences between the two sunscreen ingredients. Tumor protection factors were calculated from these results and found to be equal to 2.4 for the two preparations containing Mexoryl SX and to 1.3 for the 5% 2-EHMC preparation. These findings illustrate the efficacy of Mexoryl SX in preventing UVR-induced carcinogenesis.


Mutagenic activity in photocopies.
Extracts from several different photocopies were mutagenic in the Ames Salmonella assay. The mutagenic behavior was similar for extracts from copies and corresponding toners indicating that toners are directly responsible for the mutagenicity. The mutagenicity is caused by at least two classes of compounds which may be present either alone or in combination in any toner.